Inherited retinal degenerations (IRDs) result in the progressive and permanent death of neurons. In recent years, however, our knowledge of endogenous stem cells in the retina has opened the possibility of stimulating regeneration of lost neurons in patients suffering from IRDs. Leber's Congenital Amaurosis (LCA), Bardet-Biedl Syndrome, and Retinitis Pigmentosa are among the most common form of IRDs. Mutations in CEP290 are one of the most common causes of LCA, while mutations in BBS2 contribute to BBS and mutations in the EYS gene cause RP. We demonstrate that zebrafish with mutations in the either cep290, bbs2, or eys genes undergo a progressive cone degeneration with evidence of rod dysfunction. Unlike mammals, zebrafish have the innate ability to regenerate retinal neurons when they are damaged or lost. In response to retinal injury, zebrafish exhibit a robust capability of regenerating lost neurons, including photoreceptors. Retinal damage causes release of growth factors and inflammatory cytokines that trigger Mller glia to divide and generate multipotent retinal progenitor cells that regenerate lost neurons. Central to this process is a reprogramming event that involves activation of Stat3. While robust regeneration occurs following acute injury, evidence from the literature and preliminary data indicate that regeneration does not occur in zebrafish with inherited forms of retinal degeneration, such as the cep290-/-, bbs2-/-, or eys-/- mutants. These observations suggest that Mller glia respond differently to acute vs. inherited forms of retinal injury and that regeneration is only triggered when the degree of retinal injury crosses a ?damage threshold? within a temporal window. In zebrafish degeneration mutants there is widespread proliferation of rod progenitor cells. However, Mller glia, which are the source of cone progenitors, fail to proliferate. Using what is known about mechanisms involved in regeneration after acute retinal injury in zebrafish, we will test components of these signaling pathways to determine if they are activated in Mller cells of these photoreceptor degeneration mutants. In particular, we will focus on pathways that converge to activate Stat3. Using RNAseq on purified Muller glia from these degeneration mutants, we will investigate how degeneration and inflammation alter the transcriptome of Muller glia. Finally, we will use pharmacological and genetic approaches to suppress immune cell activity and understand the role of microglia and macrophages on degeneration and regeneration. Understanding the mechanisms that underpin retinal regeneration in multiple zebrafish disease models will generate novel hypotheses that can ultimately be translated into humans with retinal degenerative diseases.